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03 August 2011

New paper in Nature Structural and Molecular Biology

Scientists have discovered the origin of a new group of small RNAs that are produced when human cells are “reading” genes in their DNA. This discovery can lead to a better understandingof how human genes are controlled and how their mRNA products are removed in both health and disease.

The Sandelin group from the Bioinformatics Centre at the Department of Biology & BRIC at Copenhagen University in close collaboration with laboratoriesfrom Aarhus and Regensburg (Germany) have studied the origin of a class of RNAmolecules in human, collectively called small RNAs. These small RNAs occur at the same places as human genes in our DNA, and their function and origin hasuntil now been a mystery.

By sequencing millions of small RNAs, the scientists showed that the most probable origin of the majority of small RNAs are as either a failed attempt at producing the much longer RNA molecules from a complete gene or as degradation products of the these longer gene-RNA molecules. These can both be considered “biological noise” in the sense that they are either merely a bi-product of the process or in the latter case that the cell is done using the longer RNA and the short RNAs are merely an intermediary step towards complete degradation.

In a few cases however, this degradation process has been “hijacked” and instead produce small RNAs that are likely functional and have roles inregulating other genes. Evidence towards which enzymes are responsible for this degradation was found and in the future these may be revealed as new key players in the regulation of human gene activity. The study appears in this month’sedition of the renowned journal Nature Structural and Molecular Biology (http://dx.doi.org/10.1038/nsmb.2091))

 

 

Background information: the ocean

It used to be so easy: For decades ribonucleic acid (RNA) was regarded apolymeric molecule whose role was, among other things, to serve as a messenger (hence commonly called mRNA) that transmits the genetic information contained in DNA inside the cell nucleus to the outside as a translation template for the production of proteins. For its own production, in a process known astranscription, mRNAs rely on a molecular machine, the so-called RNA polymeraseII (RNAPII). Recent technological advances now allow probing the total cellular RNA content to an unprecedented depth. Two of the most burning questions have been the origin and purpose – if any – of a highly abundant and diverse set of RNAs that, like mRNAs, are derived from genes, but unlike mRNAs are muchshorter: These sRNAs are only up to ~25 nucleotides long, while mRNAs can easily reach lengths in the thousands.

 

Small RNAs: nothingbut driftwood?

By investigating millions of sRNAs, some from cells depleted of RNAdegradation enzymes (e.g. Xrn1 and Xrn2) to make degradation intermediates morestable and some from specific cellular compartments, the likely origins of these RNAs were pin-pointed. To gain more mechanistic insight, these findings wer ethen compared to previously published maps of the position of RNAPII and the large DNA structures, nucleosomes. As mRNA is produced, its front end passes through a tunnel formed by RNAPII itself. Interestingly, the predominant length of the observed sRNAs (around 20 nucleotides) corresponds exactly to the numbe rof nucleotides that the tunnel can accommodate. These results paint a picture where a sizable fraction of sRNAs are generated when transcription is aborted and the unfinished mRNA is attacked by degrading enzymes while still attached to RNAPII, leaving behind only those ~20-nucleotide fragments that aresheltered in the tunnel.

 

It has been known for a while that transcription is especially prone to fail early at the very start of a gene, and indeed it is here where most sRNAs originate.The scientist could also identify many sRNAs that stem from sites further down the gene as byproducts of a process known as splicing, another event that is critical for the generation of most functional mRNAs, or as remnants of defects in this process. Icing on the cake, the team identified both some of the splicing-associated sRNAs and sRNAs originating from the very ends of protein-coding genes as rare subclasses of sRNAs that show promises of being functional, as they were associated with the Argonaute proteins that mediate the gene-regulatory functions of microRNAs. As a whole, these new observations support the notion that many mRNAs remain unfinished and instead are rapidly discarded. Rather than being merely wasteful, it is thought that this processis one of the many ways cells shield themselves against the potentially deleterious effects of faulty mRNAs, true to the precautionary principle “better safe than sorry”.

The scientists now look forward to studying these mechanisms in greater detail by both further genome-wide studies and more rigorous investigation of selected genes – efforts they hope will reveal how RNAPII is controlled during early transcription.

The research was led in equal parts by the groups of Associate Professor Albin Sandelin at Copenhagen University’s Bioinformatics Centre, Department of Biology and the Biotech Research and Innovation Centre (BRIC) and Professor Torben Heick Jensen, Director of the Centre for mRNP Biogenesis andMetabolism, Department of Molecular Biology, Aarhus University. The first authorship was split three-ways between postdoctoral fellows Eivind Valen(University of Copenhagen) and Pascal Preker, as well as graduate student Peter R. Refsing (both at University of Aarhus). Professor Gunter Meister and members of his group at the Department of Biochemistry, University of Regensburg, joined them in their effort.

 

For further information, please contact AlbinSandelin (albin@binf.ku.dk,phone +45 353 21285 , Centre for Bioinformatics, www.binf.ku.dk)